Administration of 3'-Azido-3'-Deoxythymidine, an Inhibitor of HTLV-Iii/Lav Replication, to Patients With Aids or Aids-Related Complex

Yarchoan, Robert; Weinhold, Kent J.; Lyerly, H. Kim; Gelmann, Edward P.; Blum, R.; Shearer, Gene M.; Mitsuya, Hiroaki; Collins, Jerry M.; Myers, Charles E.; Klecker, Raymond W.; Markham, Phillip D.; Durack, David T.; Lehrman, Sandra Nusinoff; Barry, David W.; Fischl, Margaret A.; Gallo, Robert C.; Bolognesi, Dani P.; Broder, Samuel

doi:10.1016/s0140-6736(86)92808-4

Cited by 760 publications

(194 citation statements)

References 13 publications

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“…To date, many such molecules have been identified, including 3′-azido-3′-deoxythymidine (AZT), which inhibits human immunodeficiency virus (HIV)-1 by interfering with DNA synthesis (43), PIPER (N,N′-bis[2-(1-piperidino) ethyl]-3,4,9,10-perylenetetra-carboxylic diimide), which binds to G-quadruplexes (44), and epigallocatechin-3-gallate (EGCG), which is derived from polyphenols in green tea (45). Of these, EGCG has been reported to inhibit the invasion and proliferation of oral cancer cells (46,47).…”

Section: Discussionmentioning

confidence: 99%

Telomerase activity in the occurrence and progression of oral squamous cell carcinoma

et al. 2015

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Chronic inflammation is considered to be one of the risk factors for carcinogenesis. It was recently reported that telomerase plays an important role in inducing such chronic inflammation. Although high telomerase activity is detected in cancer tissues, the activator of telomerase is still unknown. In this study, we used an immunohistochemical method to examine the expression of human telomerase reverse transcriptase (hTERT) in the dysplasia-carcinoma sequence in the oral cavity. Furthermore, the effects of inflammatory cytokines on the telomerase activity and migration of oral cancer cell lines (Ca9-22, HSC-3, and HSC-4) were examined. Immunoreactivity for hTERT was observed in squamous intraepithelial neoplasia 3 and squamous cell carcinoma. Telomerase activity in Ca9

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Section: Discussionmentioning

confidence: 99%

Telomerase activity in the occurrence and progression of oral squamous cell carcinoma

et al. 2015

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“…In addition to its demonstrated value as an antiviral agent for the treatment of HIV-1 infection (36,37), AZT also has the potential to modulate cytopathic HIV-1 infection of T cells to a form'that is persistent and noncytopathic. This feature of drug action is due to inhibiting reinfection of already infected cells and requires lower concentrations of drug than are necessary to inhibit primary infection .…”

Section: Discussionmentioning

confidence: 99%

Reinfection results in accumulation of unintegrated viral DNA in cytopathic and persistent human immunodeficiency virus type 1 infection of CEM cells.

Pauza

Galindo

1990

The Journal of Experimental Medicine

105

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SummaryHigh levels of unintegrated viral DNA accumulate during human immunodeficiency virus type 1 (HIV 1) infection of CEM T cells. Reinfection of already infected cells is required to attain these levels and reinfection also promotes the development of HIV-induced cytopathology. Rates of virus production, however, are independent of the accumulation of unintegrated viral DNA . Neutralizing antibody added soon after infection reduced viral DNA levels without appreciably affecting the production of cell-free viral p24 antigen or reverse transcriptase activity. Only 50 pM AZT were required to reduce the accumulation of unintegrated viral DNA by 50% in contrast to the 25 nM required to inhibit virus production by 50%. Cytopathology,-as measured by number of syncytia in infected cell cultures, was correlated with highly elevated levels of unintegrated viral DNA . The minimal levels of unintegrated viral DNA present constitutively in the persistently infected HCEM cell line were consonant with the absence of cytopathic effects in these cells. These data demonstrate that inhibiting the reinfection of already infected cells modulates cytopathic HIV-1 infection to a form that is persistent and noncytopathic.Depletion of CD4 T lymphocytes is an important feature of the natural history of HIV-1 infection (1, 2). Reduced numbers in this cell population predict disease progression (1-3) and are likely to contribute to immunodeficiency (4) . HIV-1 infection in vitro is rytopathic for T lymphocytes (5-7) and T lymphoid cell lines (8,9). This cytopathology occurs by the formation of syncytia when infected and uninfected CD4+ cells are admixed (8, 9) and direct cell killing by a mechanism independent of cell fusion (10) . Based on the cytopathic effects of HIV-1 infection of T cells in vitro, this mechanism was proposed to be a crucial feature of viral pathogenesis in AIDS (6,5,11, 12) . In this study, we have examined the role of reinfection and viral DNA accumulation in cytopathic and persistent HIV-1 infection of the CEM cell line.Host-pathogen interactions leading to cytopathology have been characterized extensively in avian retrovirus models. The accumulation of high levels of unintegrated viral DNA is a recognized feature of rytopathic infection by these retroviruses (13, 14) and was also shown to be an important marker of pathogenesis in the case of feline leukemia virus infection of cats (15) and equine infectious anemia virus infection of horses (16).Unintegrated viral DNA is generated by reverse transcription of infecting viral RNA . A linear viral DNA molecule 1035 flanked at both ends by long terminal repeat (LTR)t sequences (17) is generally found to be the most abundant form of unintegrated viral DNA . Intramolecular recombination between the LTR sequences then generates a circular molecule with one LTR that is of intermediate abundance . A circular DNA form with two LTR seems to arise via direct ligation of the ends of a linear molecule and is the least abundant species . Importantly, these DNA species are pro...

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“…Antiretroviral therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infection has proven effective in increasing the length and quality of life of infected individuals (6,29,30). However, after approximately 2 years many patients become refractory to therapy and their symptoms return (5,20,21).…”

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confidence: 99%

Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine

Fitzgibbon

Howell

Haberzettl

et al. 1992

Antimicrob Agents Chemother

185

104

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To investigate whether human immunodeficiency virus type 1 pol gene mutations are selected during prolonged 2',3'-dideoxycytidine (ddC) therapy, we used the polymerase chain reaction to amplify a portion of the reverse transcriptase segment of the pol gene from the peripheral blood mononuclear cell DNA of a patient with AIDS before and after an 80-week course of ddC therapy. The consensus sequence from the second sample contained a unique double mutation (ACT to GAT) in the codon for reverse transcriptase amino acid 69, causing substitution of aspartic acid (Asp) for the wild-type threonine (Thr). A mutation (ACA to ATA) also occurred in the codon for position 165, causing substitution of isoleucine (Ile) for Thr. The GAT (Asp) codon was introduced into the pol gene of a molecular clone of human immunodeficiency virus via site-directed mutagenesis. Following transfection, mutant and wild-type viruses were tested for susceptibility to ddC by a plaque reduction assay. The mutant virus was fivefold less susceptible to ddC than the wild type; crossresistance to 3'-azido-3'-deoxythymidine or 2'3'-dideoxyinosine was not found. The lle-165 mutation did not confer additional ddC resistance. The Asp-69 substitution may have contributed to the generation of resistant virus in this patient.

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Administration of 3'-Azido-3'-Deoxythymidine, an Inhibitor of HTLV-Iii/Lav Replication, to Patients With Aids or Aids-Related Complex

Cited by 760 publications

References 13 publications

Telomerase activity in the occurrence and progression of oral squamous cell carcinoma

Telomerase activity in the occurrence and progression of oral squamous cell carcinoma

Reinfection results in accumulation of unintegrated viral DNA in cytopathic and persistent human immunodeficiency virus type 1 infection of CEM cells.

Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine

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